The long range plan of this research project is to understand the pathomechanisms of human cutaneous hypersensitivity granulomas, such as sarcoidosis, metal-induced granulomas and tuberculoid leprosy. These diseases create a disabling and crippling condition in patients, and because of a lack of information about the disease process patients do not receive adequate treatment. A new cutaneous model for granulomatous disease has been developed which closely mimics human skin granulomas. It will be used to probe basic pathomechanisms and fill gaps in our knowledge. The hypothesis t be tested proposes that hypersensitivity granulomas evolve from two overlapping and perhaps interdependent events, an initiation event which is independent of the T-cell mediated immune system and promotion event which embodies T-cell mechanisms to expand the efflorescence of clinically apparent granulomas. Using athymic and euthymic littermates, direct experiments are planned to demonstrate that 1) granulomas can be initiated without eliciting evidence of T-cell maturation or function and 2) the initiated granulomatous reaction can be expanded by T-cell functions in euthymic mice and by supplementation of T-cell functions in athymic mice. Furthermore, we will attempt to biochemically characterize both granuloma "initiating" and "promoting" factors. Because there is a need to biochemically distinguish hypersensitivity granulomas from chronic inflammation and foreign body reactions in skin, additional effort will be directed to test some recently described enzymes from activated macrophages in the cutaneous model to better define organized granulomatous inflammation in biochemical terms. It has been recognized that biochemical properties of granulomas in skin may differ from granulomatous lesions in other body sites. In earlier studies eosinophilia along with granuloma formation were transferred by viable cells from euthymic mice to both athymic and euthymic mice. "Eosinophilia transfer factor" which becomes inactive by freeze-drying will be separately isolated from fresh granulomas. It is expected that the findings from the project will provide information about how organized epithelioid cell granulomas are formed in skin and will offer a more cohesive view of the total disease process.